PFIZER 150-602 PROJECT SUMMARY

Name of Drug: Voriconazole

Pharmaceutical Manufacturer/Sponsor: Pfizer, Inc.

Study Title: AN OPEN RANDOMIZED COMPARATIVE MULTI CENTER STUDY OF THE EFFICACY, SAFETY, AND TOLERATION OF VORICONAZOLE VERSUS AMPHOTERICIN B FOLLOWED BY OTHER LICENSED ANTIFUNGAL THERAPY IN THE TREATMENT OF ACUTE INVASIVE ASPERGILLOSIS IN IMMUNOCOMPROMISED PATIENTS

BACKGROUND:

Drug Characteristics:

Plasma protein binding is about 70% in all species
Essentially cleared by hepatic metabolism, with 7% excreted in urine or feces unchanged
Characterized by non-linear, dose-dependent pharmacokinetics
Fungicidal: inhibition of fungal cytochrome P-450 dependent 14 a-sterol demethylase, and essential enzyme in ergosterol biosynthesis
Rapidly absorbed (Tmax 1-2 hours), bioavailability reduced by food
Significant accumulation on multiple dosing due to saturation of first pass metabolism and systemic clearance

Voriconazole Toxicity

Visual disturbance: enhanced brightness or blurry vision 14.5%
Raised Liver function tests (LFTs), bilirubin, alkaline phosphatase (potentially indicative of hepatic cholestasis).
Skin reactions: erythema, rash 3.8%, photosensitivity

The most frequent reported side-effect in patients that have already received voriconazole was a Abrightness@ in vision that usually lasted less than 2 hour. The next most commonly reported side-effect was a rise in the blood tests from the liver. Other less frequently reported side-effects include skin rash and hypoglycemia (low blood sugar).

Amphotericin B Toxicity

The known side effects of amphotericin B include a decrease in kidney function, hypotension (low blood pressure), fever, chills, nausea, shaking, vomiting, anemia (low blood count) and hypokalemia (low levels of potassium).

ASSUMPTIONS BEHIND PRESENT STUDY:

The azoles have improved the therapy of opp. Fungal infections, but may suffer in deficiencies in spectrum or pharmacokinetic profile or the availability of parenteral formulations. The study drug, Voriconazole combines a wide spectrum of antifungal activity with low protein binding in both oral and parenteral formulations, high blood concentrations, and good tissue distribution.

The purpose of this research study is to determine if voriconazole, a research treatment, is safe, effective, and tolerated in the treatment of aspergillosis, a fungal infection. This research study is also designed to compare voriconazole, the research treatment to amphotericin B, which is the current drug treatment for aspergillosis. As of June 1996, voriconazole had been given to 726 healthy volunteers or patients with fungal infections. Most of the volunteers and patients were treated in research studies conducted in Europe.

STUDY DESIGN:

Class: Phase III, multi-center, open-label, randomized, parallel group study

Patient Type:

Males or females, twelve years of age or older

Definite or Probable diagnosis of acute invasive aspergillosis

Definite: clinical and radiological evidence suggestive of aspergillosis supported by positive histopathology and/or culture from a specimen obtained by an invasive procedure.

Probable: clinical and radiological evidence suggestive of aspergillosis supported by positive histopathology and/or culture from a bronchoalveolar lavage specimen or non-invasive site culture.

Treatment Groups and Schedule:

Total N=284 with approximately n=23 enrolled at this site

Number of treatment arms = 2

Study duration = treatment maximum 12 weeks, monitored for an additional 4 weeks (16 weeks total)

Treatment group A = IV Amphotericin B at least 1 mg/kg daily for duration

Treatment group B = IV Voriconazole loading dose of 6mg/kg Q 12h for first 24 hours, followed by 3mg/kg Q 12h for the next 7-28 days as deter mined by PI. Following IV Voriconazole Tx, subject receives 200 mg BID. Maximum total duration of Tx (oral + IV) will be 12 weeks.

Frequency and Evaluations:

Each patient will be hospitalized at the beginning of study treatment and therefore will be under continuous medical surveillance during the early period of Tx.

Provision for Drug/Follow-up at Study Completion:

Individual patients may require additional therapy with Voriconazole beyond the 12 weeks allowed in this protocol. In such circumstances, extended treatment with Voriconazole will be made available under a separate protocol after discussion and approval by the Pfizer clinical project manager.

Abstract prepared by: Dawn Morgado, MPH

Date: 4/27/97

Protocol Version 4/2/97